Process for the preparation of (r)-2-alkyl-3-phenyl-1-propanols

ABSTRACT

Compounds of formula (I), wherein R 1  and R 2  are, independently of one another, H,C 1 -C 6 alkyl, C 1 -C 6 halogenalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, or C 1 -C 6 alkoxy-C 1 -C 6 alkyloxy, and R 3  is C 1 -C 6 alkyl, are obtainable in high yiedls by stereoselective addition of R 3 -substituted propionic acid esters to R 1 - and R 2 -substituted benzaldehydes of formula R—CHO to form corresponding 3-R-3-hydroxy-2-R 3 -propionic acid esters, conversion of the OH group to a leaving group, subsequent regioselective elimination to form 3-R-2-R 3 -propenic acid esters, and reduction to corresponding 3-R-2-R 3 -allyl alcohols and their enantioselective hydrogenation, wherein R is (a).

[0001] The invention relates to a stereoselective process for thepreparation of (R)-2-alkyl-3-phenyl-1-propanols and new intermediateproducts obtained in the process steps.

[0002] In EP-A-0 678 503, δ-amino-γ-hydroxy-ω-aryl-alkanecarboxamidesare described which exhibit renin-inhibiting properties and could beused as antihypertensive agents in pharmaceutical preparations. Themanufacturing processes described are unsatisfactory in terms of thenumber of process steps and yields and are not suitable for anindustrial process. A disadvantage of these processes is also that thetotal yields of pure diastereomers that are obtainable are too small.

[0003] In a new process, one starts from 2,7-dialkyl-8-aryl-4-octenoylamides, whose double bond is simultaneously halogenated in the5-position and hydroxylated in the 4-position under lactonization, thenthe halogen is substituted by azide, the lactone amidated and the azidethen transferred to the amine group. The desired alkanecarboxamides areobtained with the new process both in high total yields and in a highdegree of purity, and selectively pure diastereomers can be prepared.The halolactonization of process step a), the azidation of process stepb), and the azide reduction of process step d) are described by P.Herold in the Journal of Organic Chemistry, Vol. 54 (1989), pages1178-1185.

[0004] The 2,7-dialkyl-8-aryl-4-octenoyl amides may correspond forexample to formula A,

[0005] and especially to formula Al

[0006] wherein R₁ and R₂ are, independently of one another, H,C₁-C₆alkyl, C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, R₃ is C₁-C₆alkyl, R₄ is C₁-C₆alkyl, R₆ isC₁-C₆alkyl, R₅ is C₁-C₆alkyl or C₁-C₆alkoxy, or R₅ and R₆ together aretetramethylene, pentamethylene, 3-oxa-1,5-pentylene or —CH₂CH₂O—C(O)—substituted if necessary with C₁-C₄alkyl, phenyl or benzyl.

[0007] The compounds of formulae A and Al are obtainable by reacting acompound of formula B

[0008] as racemate or enantiomer, with a compound of formula C, asracemate or enantiomer,

[0009] wherein R₁ to R₄, R₅ and R₆ are as defined above, Y is Cl, Br orI and Z is Cl, Br or I, in the presence of an alkali metal or alkalineearth metal. Y and Z are preferably Br and especially Cl.

[0010] The compounds of formula B are known from EP-A-0 678 503. Thecompounds of formula C may be prepared from amidation of thecorresponding carbonic esters, amides, or halides. The formation ofcarboxamides from carbonic esters and amines in the presence of trialkylaluminium or dialkyl aluminium halide, for example using trimethylaluminium or dimethyl aluminium chloride, is described by S. M. Weinrebin Org. Synthesis, VI, page 49 (1988). The carbonic esters areobtainable by the reaction of trans-1,3-dihalogenpropene (for example,trans-1,3-dichlorepropene) with corresponding carbonic esters in thepresence of strong bases, for example alkali metal amides.

[0011] A satisfactory solution for the stereoselective preparation ofcompounds of formula B has not yet been found, especially with regard toan industrial process. Surprisingly it has now been found that2-alkyl-3-phenylpropionic acids can be stereoselectively prepared withhigh yields in only three process steps. When suitably substitutedbenzaldehydes are condensed with carbonic esters to form2-alkyl-3-hydroxy-3-phenylpropionic acid esters, the desireddiastereomers are obtainable in surprisingly high yields mostly ascrystalline compounds which can be readily isolated. After conversion ofthe hydroxy group to a leaving group, 2-alkylcinnamic acid esters arethen formed by elimination with strong bases with surprisingly highregioselectivity. The allyl alcohols obtained after hydrogenation can inturn be hydrogenated in the presence of certain catalysts to formpractically enantiomer-pure 2-alkyl-3-phenyl-1-propanols. These alcoholscan then be converted by halogenation to the compounds of formula B in amanner known per se.

[0012] The object of the invention is a process for the preparation ofcompounds of formula I,

[0013] wherein R₁ and R₂ are, independently of one another, H,C₁-C₆alkyl, C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆-alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, and R₃ is C₁-C₆-alkyl, comprising

[0014] a) the reaction of a compound of formula II

[0015]  wherein R₁ and R₂ are as defined above, with a compound offormula III,

[0016]  wherein R₃ is as defined above, to form a compound of formulaIV,

[0017]  wherein R₇ is C₁-C₁₂alkyl, C₃-C₈cycloalkyl, phenyl or benzyl,

[0018] b) the isolation of the crystalline compound of formula IV, theconversion of the OH group to a leaving group, and the reaction of acompound containing a leaving group in the presence of a strong base toform a compound of formula V,

[0019] c) the reduction of carbonic esters of formula V to form thealcohol of formula VI,

[0020] d) the hydrogenation of the alcohol of formula VI in the presenceof hydrogen and catalytic quantities of a metal complex as asymmetrichydrogenation catalyst, comprising metals from the group of ruthenium,rhodium and iridium, to which the chiral bidentate ligands are bonded,to form a compound of formula I.

[0021] R₁ and R₂ may be a linear or branched alkyl and preferablycomprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl,n-, i- and t-butyl, pentyl and hexyl.

[0022] R₁ and R₂ may be a linear or branched halogenalkyl and preferablycomprise 1 to 4 C atoms, 1 or 2 C atoms being especially preferred.Examples are fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and2,2,2-trifluoroethyl.

[0023] R₁ and R₂ may be a linear or branched alkoxy and preferablycomprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- andi-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

[0024] R₁ and R₂ may be a linear or branched alkoxyalkyl. The alkoxygroup preferably comprises 1 to 4 and especially 1 or 2 C atoms, and thealkyl group preferably comprises 1 to 4 C atoms. Examples aremethoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl,methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl,1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl,propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and1-butyloxyeth-2-yl.

[0025] R₁ and R₂ may be linear or branched C₁-C₆alkoxy-C₁-C₆alkyloxy.The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 Catoms, and the alkyloxy group preferably comprises 1 to 4 C atoms.Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy,1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy,methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy,1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy,ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy,1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.

[0026] In a preferred embodiment, R₁ is methoxy-C₁-C₄alkyloxy orethoxy-C₁-C₄alkyloxy, and R₂ is preferably methoxy or ethoxy. Quiteespecially preferred are compounds of formula I, wherein R₁ is1-methoxyprop-3-yloxy and R₂ is methoxy.

[0027] R₃ may be a linear or branched alkyl and preferably comprise 1 to4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- andt-butyl, pentyl and hexyl. In a preferred embodiment, R₃ in compounds offormula I is isopropyl.

[0028] Especially preferred are compounds of formula I wherein R₁ ismethoxy-n-propoxy, R₂ is methoxy and R₃ is isopropyl.

[0029] R₇ is preferably C₁-C₆alkyl, C₁-C₄alkyl being especiallypreferred; some examples are methyl, ethyl, n-propyl and n-butyl.

[0030] The starting compounds of formulae II and III used in processstep a) are known or can be prepared in a manner similar to knownprocesses. Compounds of formula II are described in EP-A 0 678 503. Thereaction is advantageously carried out at low temperatures, for example0-40° C., in the presence of at least equivalent quantities of strongbases. The reaction is further expediently carried out in a solvent,ethers such as diethyl ether, tetrahydrofuran and dioxane beingespecially suitable. Suitable strong bases are in particular alkalimetal alcoholates and secondary amides, such as lithiumdiisopropylamide.

[0031] The desired diastereomer of formula IV is surprisingly formed upto about 75%. The compounds of formula IV are surprisingly crystallineand can therefore be readily isolated without any substantial losses bymeans of extraction and crystallization.

[0032] The conversion of the OH group to a leaving group in reactionstep b) is known per se. Reaction with carboxylic acids or sulfonicacids, or their anhydrides (acylation), is especially suitable. Someexamples of carboxylic acids are formic acid, acetic acid, propionicacid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid,methylsulfonic acid and trifluoromethylsulfonic acid. The use of aceticacid anhydride has proved especially successful. The elimination isexpediently carried out in the presence of strong bases, alkali metalalcoholates such as potassium t-butylate being especially suitable. Thepresence of solvents such as ethers is expedient. The reaction isadvantageously carried out at low temperatures, for example 0-40° C. Itis of advantage to conduct the elimination reaction directly in thereaction mixture for acylation. The elimination leads to the desired zisomers with surprisingly high regioselectivity. These isomers arecrystalline and can therefore be readily isolated without anysubstantial losses by means of extraction and crystallization. Theyields are above 80%.

[0033] Process step d) is preferably carried out at low temperatures,for example −40° C. to 0° C., and advantageously in a solvent. Suitablesolvents are, for example, hydrocarbons (pentane, cyclohexane,methylcyclohexane, benzene, toluene and xylene). For hydrogenation,metal hydrides are expediently used in at least equimolar quantities,for example LiH, NaH, NaBH₄, LiAlH₄, and alkyl metal hydrides such asmethyl, ethyl, or isopropyl aluminium dihydride or tin trihydride,dimethyl, diethyl, triisopropyl or triisobutyl aluminium hydride or tindihydride, and tributyl tin hydride. The compounds can be isolated bymeans of extraction and purified by means of distillation. The yieldsamount to more than 90%.

[0034] The asymmetric hydrogenation in process step d) ofα,β-unsaturated carboxylic acids with homogeneous, asymmetrichydrogenation catalysts is known per se and described for example byJohn M. Brown in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.),Comprehensive Asymmetric Catalysis I to III, Springer Verlag, 1999,pages 121 to 182. Especially effective are ruthenium and rhodiumcatalysts. Chiral ditertiary diphosphines whose phosphine groups in the1,2, 1,3 or 1,4 position are bonded to a C₂-C₄carbon chain are oftenused as ligands. The skeletal structures of the chiral ditertiarydiphosphines may be acyclic, monocyclic or polycyclic. The phosphinegroups may be substituted with the same or with different, preferablythe same, substituents selected from the group of C₁-C₈alkyl,C₃-C₈cycloalkyl, C₆-C₁₂aryl, and C₆-C₁₂aryl- C₁-C₄alkyl. Cycloalkyl andaryl may be unsubstituted or substituted with C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkyl or C-C₁₂secondary amino. Suitable phosphine groups arealso phosphanyl, preferably five-member phosphanyl, which if necessaryis substituted in one or both α-positions with C₁-C₄alkyl orC₁-C₄alkoxy.

[0035] Some examples of chiral ditertiary diphosphines are (R″₂P is forexample diphenylphosphino or dicyclohexylphosphino, substituted ifnecessary) 1,2-Di-R″₂P-propane, 2,3-Di-R″₂P-butane,1,2-Di-R″₂P-norbornane or -norbornadiene, 1,2-Di-R″₂P-cyclopentane,1,2-Di-R″₂P—N-methylpyrrolidine, 2,2′-Di-R″₂P-biphenyl or -binaphthyl,2,2′-Di-R″₂P-6-methyl or -6,6′-dimethylbiphenyl, 2,2′-Di-R″₂P-6-methoxyor -6,6′-dimethoxybiphenyl, and 1-(α-R″₂P-ethyl)-2-R″₂P-ferrocene.

[0036] Good optical yields are achieved using metal complexes of formulaVII or VIIa,

[LMeYZ]  (VII),

[IMeY]⁺E⁻  (VIIa),

[0037] wherein

[0038] Me is rhodium;

[0039] Y stands for two olefins or one diene;

[0040] Z is Cl, Br or I;

[0041] E⁻ is the anion of an oxygen acid or a complex acid; and

[0042] L is a chiral ligand from the group of ditertiary diphosphines,in which the phosphine groups are bonded to a C₂-C₄ chain of thediphosphine backbone chain, and the diphosphine forms a five toseven-member ring together with the rhodium atom.

[0043] Where Y stands for two olefins, they may be C₂-C₁₂ olefins,C₂-C₆olefins being preferred and C₂-C₄olefins being especiallypreferred. Examples are propene, but-1-ene and especially ethylene. Thediene may comprise 5 to 12 and preferably 5 to 8 C atoms and may be anacyclic, cyclic or polycyclic diene. The two olefin groups of the dieneare preferably linked by one or two CH₂ groups. Examples are1,3-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4-cyclohexadiene, 1,4-or 1,5-heptadiene, 1,4- or 1,5-cycloheptadiene, 1,4- or 1,5-octadiene,1,4- or 1,5-cyclooctadiene and norbornadiene. Y represents preferablytwo ethylene or 1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.

[0044] In formula VII, Z is preferably Cl or Br. Examples of E₁ are ClO₄⁻, CF₃SO₃ ⁻, CH₃SO₃ ⁻, HSO₄ ⁻, BF₄ ⁻, B(phenyl)₄ ⁻, PF₆ ⁻, SbCl₆ ⁻, AsF₆⁻ or SbF₆ ⁻.

[0045] It was found that ligands with a biphenyl backbone are especiallysuitable for the asymmetric hydrogenation of compounds of formula VI.With these ligands in the metal complexes of formulae VII and VIIa,optical yields of at least 95% ee can be achieved, which represents asubstantial cost saving for manufacture on an industrial scale. Inprocess step d), therefore, it is preferred to use metal complexes offormulae VII and VIIa, wherein L represents the ligands of formula VIII,

[0046] wherein

[0047] m and n in each case are 0 or an integer from 1 to 4, and R₈ andR₉ are hydrogen or the same or different substituents, selected from theC₁-C₄alkyl and C₁-C₄alkoxy group; and

[0048] X₁ and X₂ are, independently of one another, secondary phosphino.

[0049] Substituents are preferably bonded in the 6 position or the 6,6′positions.

[0050] As an alkyl, R₈ and R₉ may preferably comprise 1 to 2 C atoms.Linear alkyl is preferred. Examples of R₈ and R₉ as an alkyl are methyl,ethyl, n- and i-propyl, n-, i- and t-butyl. Methyl and ethyl arepreferred, and methyl is especially preferred.

[0051] As an alkoxy, R₈ and R₉ may preferably comprise 1 to 2 C atoms.Linear alkoxy is preferred. Examples of Re and R₉ as an alkoxy aremethoxy, ethoxy, n- and i-propoxy, n-, i-und t-butoxy. Methoxy andethoxy are preferred and methoxy is especially preferred.

[0052] The X₁ and X₂ groups may be different or preferably the same andcorrespond to formula PR₁₀R₁₁, wherein R₁₀ and R₁₁ are the same ordifferent and represent branched C₃-C₈alkyl, C₃-C₈cycloalkyl, orunsubstituted or phenyl substituted with one to three C₁-C₄alkyl,C₁-C₄-alkoxy, or —CF₃.

[0053] Special preference is for ligands of formulae VIII, wherein X₁and X₂ are a PR₁₀R₁₁ group, wherein R₁₀ and R₁₁ in each case arecyclobutyl, cyclopentyl, cyclohexyl, phenyl or phenyl substituted with 1or 2 methyl, methoxy or CF₃.

[0054] The metal complexes used as catalysts may be added as separatelyprepared isolated compounds, or also formed in situ before the reactionand then mixed with the substrate to be hydrogenated. It may beadvantageous in the reaction using isolated metal complexes to addadditional ligands, or in the in situ preparation to use surplusligands. The surplus may for example be up to 10 moles and preferably0.001 to 5 moles, based on the metal complexes used for the preparation.

[0055] Process step d) may be carried out at low or elevatedtemperatures, for example at temperatures from −20 to 150° C.,preferably from −10 to 100° C., temperatures of 10 to 80° C. beingespecially preferred. The optical yields are generally better at lowtemperatures than at high temperatures.

[0056] The process according to the invention may be carried out atnormal pressure or preferably under positive pressure. The pressure mayfor example range from 10⁵ to 2×10⁷ Pa (Pascal).

[0057] Catalysts are preferably used in quantities from 0.0001 to 10mol-% based on the compound to be hydrogenated, the range 0.001 to 10mol-% being especially preferred and the range 0.01 to 5 mol-% beingpreferred in particular.

[0058] The preparation of catalysts as well as process step d) and theother process steps may be carried out in the absence or the presence ofan inert solvent, wherein one solvent or a mixture of solvents may beused. Suitable solvents are, for example, aliphatic, cycloaliphatic andaromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane,methylcyclohexane, benzene, toluene, xylene), aliphatic halogenatedhydrocarbons (dichloromethane, chloroform, di- and tetrachloroethane),nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethylether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,tetrahydrofuran, dioxane, diethylene glycol monomethyl or monoethylether), ketones (acetone, methyl isobutyl ketone), carbonic esters andlactones (ethyl or methyl acetate, valerolactone), N-substituted lactams(N-methylpyrrolidone), carboxamides (dimethylamide, dimethylformamide),acyclic ureas (dimethylimidazoline), and sulfoxides and sulfones(dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide,tetramethylene sulfone) and alcohols (methanol, ethanol, propanol,butanol, ethylene glycol monomethyl ether, ethylene glycol monoethylether, diethylene glycol monomethyl ether) and water. The solvents maybe used alone or in a combination of at least two solvents.

[0059] The reaction may be carried out in the presence of co-catalysts,for example quaternary ammonium halogenides (tetrabutylammonium iodide)and/or in the presence of protonic acids, for example mineral acids.

[0060] Using the regioselective and enantioselective process accordingto the invention, the intermediate products of the formula (B) may beprepared via all process steps in yields of at least 50% by weight,based on the compounds of formula II. The high total yields make theprocess suitable for industrial use.

[0061] A further object of the invention relates to the compounds(intermediates) of formula VI,

[0062] wherein R₁, R₂ and R₃ are defined as in claim 19.

[0063] A further object of the invention relates to the compounds(intermediates) of formula IV,

[0064] wherein R₁, R₂, R₃ and R₇ are defined as in claim 22.

[0065] The embodiments and preferences described hereinabove apply forR₁, R₂, R₃ and R₇.

[0066] The following examples explain the invention in more detail.

[0067] A) Preparation of(R)-3-[4′-CH₃O-3′-(CH₃O(CH₂)₃O)-phen-1-yl]-2-isopropylpropan-1-ol (A4)

EXAMPLE A1 Preparation of

[0068]

[0069] A solution of 436 ml diisopropylamine and 2.6 l tetrahydrofuranis cooled to −20° C., and 1.234 l n-hexyl lithium (2.5 M in hexane) isadded dropwise over a period of 15 minutes. A solution of 368 g ethylisovalerate in 1.7 l tetrahydrofuran is added dropwise over a period of15 minutes at −20° C. After a further 10 minutes, a solution of 584 g4-methoxy-3-(3-methoxy-propoxy)benzaldehyde (EP 0 678 503) in 1.7 ltetrahydrofuran is added drop by drop and stirred for 40 minutes at −20°C. Then 2.15 l saturated aqueous ammonium chloride solution is addeddrop by drop and extracted with ethyl acetate (2×8 l). The organicphases are washed consecutively with 0.5 N hydrochloric acid (1×4.3 l),water (1×4.4 l) and brine (1×4.4 l). The combined organic phases aredried over sodium sulfate (1.6 kg), filtered and boiled down in a rotaryevaporator. By means of crystallization from ethyl acetate (1 l) andhexane (11 l) title compound Al is obtained from the residue as a whitesolid (656 g, 72%): ¹H-NMR (400 MHz, DMSO-d₆, δ): 0.90-1.04 (m, 9H),1.97 (m, 2H), 2.32 (m, 1H), 2.58 (m, 1H), 3.28 (s, 3H), 3.50 (m, 2H),3.74 (s, 3H), 3.82 (q, 2H), 3.98 (m, 2H), 4.57 (m, 1H), 5.30 (d, 1H),6.75-6.90 (m, 3H) ppm.

EXAMPLE A2 Preparation of

[0070]

[0071] A solution of 20 g Al and 0,4 g 4-dimethylaminopyridine in 100 mltetrahydrofuran is cooled to 0° C., 6.3 ml acetic acid anhydride isadded dropwise and the reaction mixture stirred for 1 hour. A solutionof 19.0 g potassium t-butylate in 140 ml tetrahydrofuran is added dropby drop over a period of 30 minutes at −2° C. to 0° C. and then stirredfor 2 hours at 0° C. Then 250 ml t-butyl methyl ether and 250 ml icedwater are added to the reaction mixture. The organic phase is separatedoff and the aqueous phase extracted again with 250 ml t-butyl methylether. The organic phases are washed consecutively with 250 ml water and250 ml brine. The combined organic phases are dried over magnesiumsulfate (50 g), filtered and concentrated on a rotary evaporator. Bymeans of flash chromatography (SiO₂ 60F/ethyl acetate/hexane 1:4) puretitle compound A2 is obtained from the residue as a colourless oil(17.45 g, 92.6%): ¹H-NMR (400 MHz, CDCl₃, δ): 1.26 (d, 6H), 1.35 (m,3H), 2.15 (m, 2H), 3.22 (m, 1H), 3.38 (s, 3H), 3.60 (m, 2H), 3.90 (s,3H), 4.17 (m, 2H), 4.28 (m, 2H), 6.85-7.0 (m, 3H), 7.49 (s, 1H) ppm.

EXAMPLE A3 Preparation of

[0072]

[0073] A solution of 37.0 g A2 in 410 ml toluene is cooled to −20° C.,and 229 ml diisobutyl aluminium hydride solution (1.2 M in toluene) isadded over a period of 20 minutes. The reaction mixture is stirred for 1hour at −20° C., before 220 ml methanol is slowly added. Then 1.5 l 1NHCl is added to the mixture and this is then extracted with t-butylmethyl ether (3×1 l). The organic phases are washed consecutively with1.2 l water and 1.2 l brine. The combined organic phases are dried overmagnesium sulfate, filtered and concentrated on a rotary evaporator. Bymeans of molecular distillation, title compound A3 is obtained from theresidue as a colourless oil (29.7 g, 91.8%): ¹H-NMR (400 MHz, DMSO-d₆,δ): 1.08 (d, 6H), 1.93 (m, 2H), 3.02 (m, 1H), 3.28 (s, 3H), 3.50 (m,2H), 3.85 (s, 3H), 4.02 (m, 2H), 4.10 (d, 2H), 4.77 (bs, 1H), 6.39 (s,1H), 6.78 (m, 2H), 6.93 (m, 1H) ppm.

EXAMPLE A4 Preparation of

[0074]

[0075] In a flask with a magnetic stirrer, 1.2 mg (0.0026 mmol)[Rh(norbornadiene)Cl]₂ and 3.83 mg (0.0054 mmol) (R)-(4,4′, 5, 5′, 6,6′-hexamethoxybiphenyl-2,2′-diyl) bis (diphenylphosphine) are placedunder an atmosphere of argon through repeated evacuation and purgingwith argon. Then 10 ml degassed toluene is added and stirred for 15minutes, before 3.75 g (0.01275 mol) A3 and 20 ml degassed toluene areintroduced into a 50 ml flask fitted with a stopcock and flushed withargon. With gentle heating, agitation is continued until a homogeneoussolution is formed. The catalyst and substrate solutions are forcedunder pressure via a steel capillary tube into a 50 ml steel autoclaveunder cover of argon. In 3 purge cycles (argon 20 bar/hydrogen 20 bar)the hydrogen pressure is eventually increased to 1000 bar. The autoclaveis heated to 30° C. and hydrogenation started by switching on thestirrer. The reaction can take place via hydrogen consumption (fall ofpressure in the reservoir of hydrogen). After a reaction time of 18hours, the reaction mixture is concentrated, and crude title compound A4is obtained as a slightly yellowish oil (3.75 g, quantitative): Theenantiomeric purity of the product (measured by HPLC: column ChiralcelODH 0.46×25 cm; hexane/iPrOH: 95/5; temperature: 20° C.; flow rate: 0.6ml/min; S-product: 22.9 min; R-product: 25.3 min; educt: 27.8 min; UV:210 nm) amounts to >95% ee (R).

[0076]¹H-NMR (400 MHz, CDCl₃, δ): 0.96 (m, 6H), 1.2 (m, 1H), 1.67 (m,1H), 1.90 (m, 1H), 2.12 (m, 2H), 2.48 (m, 1H), 2.68 (m, 1H), 3.40 (s,3H), 3.60 (m, 4H), 3.89 (s, 3H), 4.12 (m, 2H), 6.70-6.85 (m, 3H) ppm.

EXAMPLE A5 Preparation of A4

[0077] The procedure is analogous to that described under Example 1, butthe ligand((R)-(6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(dicyclobutylphosphine)) isused for the catalyst.

[0078] The reaction is stopped after 18 hours. The conversion amounts to100%, and enantiomeric purity is 96.3% (R).

What is claimed is:
 1. A process for the preparation of compounds offormula I,

wherein R₁ and R₂ are, independently of one another, H, C₁-C₆alkyl,C₁-C₆halogenalkyl, C₁-C₆alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl, orC₁-C₆alkoxy-C₁-C₆alkyloxy, and R₃ is C₁-C₆alkyl comprising a) thereaction of a compound of formula II

 wherein R₁ and R₂ are as defined hereinbefore, with a compound offormula III,

 wherein R₃ is as defined hereinbefore, to form a compound of formulaIV,

wherein R₇ is C₁-C₁₂alkyl, C₃-C₈cycloalkyl, phenyl or benzyl, b) theisolation of the crystalline compound of formula IV, the conversion ofthe OH group to a leaving group, and the reaction of a compoundcontaining a leaving group in the presence of a strong base to form acompound of formula V,

c) the reduction of the carbonic esters of formula V to form the alcoholof formula VI,

d) the hydrogenation of the alcohol of formula VI in the presence ofhydrogen and catalytic quantities of a metal complex as asymmetrichydrogenation catalyst, comprising metals from the group of ruthenium,rhodium and iridium, to which the chiral bidentate ligands are bonded,to form a compound of formula I.
 2. A process according to claim 1,comprising R₁ as methoxy-C₁-C₄alkyloxy or ethoxy-C₁-C₄alkyloxy and R₂ asmethoxy or ethoxy.
 3. A process according to claim 2, comprising R₁ as1-methoxyprop-3-yloxy and R₂ as methoxy.
 4. A process according to claim1, comprising R₃ as a linear or branched C₁-C₄alkyl.
 5. A processaccording to claim 4, comprising R₃ as isopropyl.
 6. A process accordingto claim 1, comprising R₁ as 1-methoxy-n-propyloxy, R₂ as methoxy, andR₃ as isopropyl.
 7. A process according to claim 1, comprising theprocessing of step a) at low temperatures in the presence of a secondarylithium amide.
 8. A process according to claim 1, comprising in step b)first acylation of the hydroxyl group and then elimination at lowtemperatures in the presence of an alkali metal alcoholate in thereaction mixture of the acylation process.
 9. A process according toclaim 1, comprising step c) being carried out at low temperatures in thepresence of metal hydrides as reduction agents.
 10. A process accordingto claim 1, comprising step d) being carried out in the presence ofmetal complexes of formula VII or VIIa as hydrogenation catalysts,[LMeYZ]  (VII), [LMeY]⁺E⁻  (VIIa), wherein Me is rhodium; Y stands fortwo olefins or one diene; Z is Cl, Br or I; E⁻ is the anion of an oxygenacid or a complex acid; and L is a chiral ligand from the ditertiarydiphosphine group, in which the phosphine groups are bonded to a C₂-C₄chain of the diphosphine backbone chain, and the diphosphine forms afive to seven-member ring together with the rhodium atom.
 11. A processaccording to claim 10, comprising L as formula VIII,

wherein m and n in each case are 0 or an integer from 1 to 4, and R₈ andR₉ are hydrogen or the same or different substituents, selected from theC₁-C₄alkyl and C₁-C₄alkoxy group; and X₁ and X₂ are, independently ofone another, secondary phosphino.
 12. A process according to claim 11,comprising the bonding of substituents in the 6 position or the 6,6′positions.
 13. A process according to claims 11 and 12, comprising R₈and R₉ as methyl, ethyl, methoxy or ethoxy.
 14. A process according toclaim 11, comprising the X₁ and X₂ groups being the same or differentand corresponding to formula —PR₁₀R₁₁, wherein R₁₀ and R₁₁, are the sameor different and are branched C₃-C₈alkyl, C₃-C₈cycloalkyl, orunsubstituted phenyl or phenyl substituted with one to three C₁-C₄alkyl,C—C₄alkoxy, or —CF₃.
 15. A process according to claim 11, comprising informulae VIII n as 0, and X₁ and X₂ as a PR₁₀R₁₁ group, wherein R₁₀ andR₁₁ in each case are cyclopbutyl, cyclopentyl, cyclohexyl, phenyl orphenyl substituted with 1 or 2 methyl, methoxy or CF₃.
 16. A processaccording to claim 1, comprising step d) being carried out attemperatures of −20 to 150° C.
 17. A process according to claim 1,comprising step d) being carried out under positive pressure.
 18. Aprocess according to claim 1, comprising pressure conditions at 105 to2×10′ Pa (Pascal).
 19. Compounds of formula VI,

wherein R₁ is methoxy-C₁-C₄alkyloxy or ethoxy-C₁-C₄alkyloxy, R₂ ismethoxy or ethoxy, and R₃ is C₁-C₆alkyl.
 20. Compounds according toclaim 19, comprising R₁ as methoxy-C₁-C₄alkyloxy or ethoxy-C₁-C₄alkyloxyand R₂ as methoxy or ethoxy, and R₃ as C₁-C₄alkyl.
 21. Compoundsaccording to claim 19, comprising R₁ as 1-methoxy-n-propyloxy and R₂ asmethoxy, and R₃ as isopropyl.
 22. Compounds of formula IV,

wherein R₁ is methoxy-C₁-C₄alkyloxy or ethoxy-C₁-C₄alkyloxy, R₂ ismethoxy or ethoxy, and R₃ is C₁-C₆alkyl, and R₇ is C₁-C₁₂alkyl,C₃-C₈cycloalkyl, phenyl or benzyl.
 23. Compounds according to claim 19,comprising R₁ as methoxy-C₁-C₄alkyloxy or ethoxy-C₁-C₄alkyloxy and R₂ asmethoxy or ethoxy, R₃ as C₁-C₄alkyl, and R₇ as C₁-C₄alkyl.
 24. Compoundsaccording to claim 19, comprising R₁ as 1-methoxy-n-propyloxy and R₂ asmethoxy, R₃ as isopropyl, and R₇ as methyl or ethyl.